DCT

2:18-cv-17463

Celgene Corp v. Hetero Labs Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:18-cv-17463, D.N.J., 12/20/2018
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey based on Defendant Hetero USA, Inc. having its principal place of business in Piscataway, New Jersey, and conducting systematic and continuous business within the district. The other foreign-based Hetero entities are alleged to be subject to jurisdiction through their U.S. agent, Hetero USA.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiff's REVLIMID® (lenalidomide) drug constitutes an act of infringement of four U.S. patents covering specific crystalline forms of lenalidomide and methods of using it to treat cancer.
  • Technical Context: The technology lies in pharmaceutical formulation, specifically the identification and characterization of polymorphs—distinct crystalline forms of an active pharmaceutical ingredient—which can have significant impacts on a drug's stability, manufacturability, and bioavailability.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' submission of ANDA No. 212414 to the U.S. Food and Drug Administration (FDA). As part of that submission, Defendants filed a "Paragraph IV Certification" alleging that Plaintiff’s patents are invalid, unenforceable, or will not be infringed by the proposed generic product. Plaintiff was notified of this certification via a letter sent no earlier than November 9, 2018.

Case Timeline

Date Event
2002-05-17 Earliest Priority Date for ’363 Patent
2003-09-04 Earliest Priority Date for ’800 and ’217 Patents
2006-08-03 Earliest Priority Date for ’929 Patent
2008-12-16 ’800 Patent Issued
2008-12-23 ’363 Patent Issued
2010-12-21 ’217 Patent Issued
2014-06-03 ’929 Patent Issued
2018-11-09 Defendants Sent Paragraph IV Notice Letter to Plaintiff
2018-12-20 Complaint Filed

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 7,465,800 - "Polymorphic Forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione," Issued December 16, 2008

The Invention Explained

  • Problem Addressed: The patent's background section notes that a single chemical compound can often exist in multiple distinct solid crystalline forms, known as polymorphs ('800 Patent, col. 2:19-23). These different forms can possess varied physical properties, such as solubility, stability, and compressibility, which can significantly affect the manufacturing, formulation, and therapeutic efficacy of a drug product ('800 Patent, col. 2:39-49).
  • The Patented Solution: The invention claims to solve this problem by disclosing the discovery and characterization of several specific polymorphic forms of the compound 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione, also known as lenalidomide ('800 Patent, Abstract). The patent provides detailed analytical data, such as X-ray powder diffraction (XRPD) patterns (e.g., ’800 Patent, Fig. 6) and thermal analysis data (e.g., ’800 Patent, Fig. 9), to uniquely identify these novel crystalline forms, including a hemihydrate form designated as Form B ('800 Patent, col. 6:53-54).
  • Technical Importance: Identifying and securing patent protection for specific, stable polymorphic forms of an active pharmaceutical ingredient is critical in drug development to ensure product consistency, control bioavailability, and create a defensible intellectual property position around a commercial drug product ('800 Patent, col. 2:49-56).

Key Claims at a Glance

  • The complaint does not specify which claims it asserts, alleging infringement of "one or more" of the patent's claims (Compl. ¶35). The lead independent claims cover specific crystalline forms.
  • Independent Claim 1 consists of a single element:
    • Crystalline 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate.

U.S. Patent No. 7,855,217 - "Polymorphic Forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione," Issued December 21, 2010

The Invention Explained

  • Problem Addressed: Similar to the ’800 Patent, this patent addresses the technical challenge of producing a consistent and stable solid form of the lenalidomide drug substance for pharmaceutical use, noting that different polymorphs can affect drug safety and efficacy (’217 Patent, col. 2:40-46).
  • The Patented Solution: This invention claims solid forms of lenalidomide that are "substantially pure" with respect to a specific polymorph (’217 Patent, col. 4:32-37). It claims compositions comprising the crystalline hemihydrate form where that form constitutes a high percentage (e.g., greater than 80%) of the total solid form, thereby ensuring consistency and control over the final drug product's properties (’217 Patent, col. 16:22-34).
  • Technical Importance: Claiming a specific polymorph in a substantially pure form provides a way to protect a drug product from generic competition that might use mixtures of polymorphs or less stable forms, ensuring that the commercial product has predictable physical and therapeutic characteristics (’217 Patent, col. 2:40-49).

Key Claims at a Glance

  • The complaint alleges infringement of "one or more claims" of the patent (Compl. ¶44).
  • Independent Claim 1 contains the following essential elements:
    • A solid form of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione,
    • comprising crystalline 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione hemihydrate,
    • wherein the crystalline ... hemihydrate is present at greater than about 80% by weight of the solid form.

U.S. Patent No. 7,468,363 - "Methods for treatment of cancers using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione," Issued December 23, 2008

  • Technology Synopsis: The patent addresses the need for safe and effective treatments for cancer and diseases associated with undesired angiogenesis (’363 Patent, col. 3:8-20). It discloses methods of treating a range of specific cancers by administering a therapeutically effective amount of the compound lenalidomide, optionally in combination with a second active agent (’363 Patent, Abstract; col. 4:50-55).
  • Asserted Claims: Independent claims 1, 3, 5, 7, 9, 11, 14, 16, and 17 are directed to methods of treating various cancers.
  • Accused Features: The complaint alleges that Defendants' act of filing an ANDA to market a generic version of REVLIMID® for the same patented indications is an act of infringement (Compl. ¶53). This allegation is based on the premise that the proposed product's labeling will instruct physicians and patients to use the drug in a manner that directly infringes the patented methods of treatment.

U.S. Patent No. 8,741,929 - "Methods using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment of mantle cell lymphomas," Issued June 3, 2014

  • Technology Synopsis: The patent addresses the need for effective treatments for lymphomas, with a specific focus on mantle cell lymphoma (MCL), a distinct and often aggressive form of non-Hodgkin's lymphoma (’929 Patent, col. 2:32-40). The invention provides a method for treating, preventing, or managing MCL by administering lenalidomide, alone or in combination with other therapies (’929 Patent, Abstract; col. 2:41-47).
  • Asserted Claims: Independent claims 1 and 11 are directed to methods of treating mantle cell lymphoma.
  • Accused Features: As with the ’363 Patent, the infringement allegation centers on the filing of the ANDA, which seeks approval for a generic product that will be labeled for the treatment of mantle cell lymphoma, thereby inducing infringement of the patented methods (Compl. ¶62).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are "Hetero’s Proposed Products," which are generic lenalidomide capsules in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg dosage strengths (Compl. ¶30). The act of infringement giving rise to the suit is Defendants' submission of ANDA No. 212414 to the FDA (Compl. ¶1).

Functionality and Market Context

The action is a stylized act of infringement under the Hatch-Waxman Act, where the filing of the ANDA itself is the legal basis for the suit (Compl. ¶35). The proposed generic products contain lenalidomide, the same active ingredient as Plaintiff's REVLIMID® drug, and seek approval for commercial sale prior to the expiration of the patents-in-suit (Compl. ¶¶ 1, 30). The complaint alleges that the proposed generic products will be used to practice the patented methods of treatment and will embody the patented compositions (Compl. ¶15).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint does not provide a detailed claim chart or specific infringement theory for the asserted patents. The infringement allegations are based on the statutory act of infringement under 35 U.S.C. § 271(e)(2)(A), which arises from Defendants' submission of an ANDA seeking approval to market a generic version of Plaintiff's REVLIMID® drug product prior to the expiration of the patents-in-suit (Compl. ¶¶ 35, 44, 53, 62). The core allegation is that the commercial manufacture, use, or sale of Hetero's Proposed Products after FDA approval will directly infringe claims covering the drug composition (the ’800 and ’217 Patents) and that the proposed product labeling will induce infringement of claims covering methods of treatment (the ’363 and ’929 Patents).

  • Identified Points of Contention:
    • Scope Questions: The primary dispute for the ’800 and ’217 Patents will likely concern claim scope and technical identity. The analysis may raise the question of whether the lenalidomide active pharmaceutical ingredient (API) in Hetero’s proposed product meets the specific definitions of the claimed crystalline forms. For example, does the term "crystalline ... hemihydrate" as defined by the patent's specification read on the API characterized in Hetero's ANDA?
    • Technical Questions: A key evidentiary question for the ’800 and ’217 Patents will be one of physical characterization. What evidence does Hetero's ANDA provide (e.g., via XRPD, DSC, or other analytical techniques) regarding the polymorphic form of its lenalidomide API? For the ’217 Patent specifically, a further question is whether the concentration of the claimed hemihydrate form in the proposed product is "greater than about 80% by weight of the solid form."

V. Key Claim Terms for Construction

  • The Term: "crystalline ... hemihydrate" (’800 Patent, claim 1; ’217 Patent, claim 1)

    • Context and Importance: This term is central to the composition-of-matter claims in the ’800 and ’217 patents. Infringement will depend entirely on whether Defendants' proposed product contains this specific polymorphic form of lenalidomide. Practitioners may focus on this term because its construction will determine whether the claims are limited to a polymorph with the exact analytical characteristics disclosed in the specification.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: A party could argue for the plain and ordinary meaning of "hemihydrate" as understood in chemistry—a crystalline solid containing one molecule of water for every two molecules of the organic compound.
      • Evidence for a Narrower Interpretation: The specification explicitly identifies "Form B" as the hemihydrate form (’800 Patent, col. 7:1-5). A party would likely argue that the term "hemihydrate" is implicitly defined by the detailed characterization data provided for Form B, including its unique XRPD pattern with peaks at "approximately 16, 18, 22 and 27 degrees 2θ" (’800 Patent, col. 6:55-60), its DSC thermogram showing an endotherm at about 268° C. (’800 Patent, col. 6:65-67), and its TGA data showing a weight loss of approximately 3.1% (’800 Patent, col. 7:1-2).

  • The Term: "greater than about 80% by weight" (’217 Patent, claim 1)

    • Context and Importance: This purity limitation is critical to distinguishing the claims of the ’217 Patent. The dispute will likely center on the range of purity encompassed by "about 80%" and the analytical methods used to establish this percentage.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: A party may argue that "about" should be given a flexible interpretation to account for standard measurement error in analytical techniques used to quantify polymorphic content.
      • Evidence for a Narrower Interpretation: The specification describes techniques for analyzing mixtures of polymorphs and emphasizes the goal of producing a "substantially pure" form to ensure consistent product performance (’217 Patent, col. 4:32-45). A party could argue that the term should be construed in light of this stated goal of high purity, limiting the scope of "about" to a narrow range just below 80%.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all four patents-in-suit (Compl. ¶¶ 38-39, 47-48, 56-57, 65-66). The inducement allegation is based on the assertion that Defendants' future product labeling will instruct physicians and patients to use the generic drug for the patented indications, thereby intentionally encouraging direct infringement of the method claims. The contributory infringement allegation is based on the assertion that Defendants' product is especially adapted for an infringing use and has no substantial non-infringing use.
  • Willful Infringement: The complaint does not contain an explicit count for willful infringement. However, it alleges that Defendants have knowledge of the patents-in-suit and requests that the case be declared "exceptional" to warrant an award of attorneys' fees under 35 U.S.C. § 285 (Compl. ¶¶ 42, 51, 60, 69). These allegations are based on Defendants' knowledge of the patents as evidenced by their Paragraph IV certification and notice letter.

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of technical identity: Can Celgene prove that the lenalidomide API in Hetero’s proposed generic product, as described in its ANDA, is the same "crystalline ... hemihydrate" (Form B) characterized in the ’800 and ’217 patents, or has Hetero successfully designed around these claims by using a different polymorphic form?
  • A second central question, assuming the claimed polymorph is present, will be one of quantitative scope for the ’217 patent: Does Hetero’s product contain the claimed hemihydrate at a concentration "greater than about 80% by weight," and how will the court construe the term "about" in the context of pharmaceutical manufacturing and analytical measurement?
  • A key issue for the defense, arising from the Paragraph IV certification, will be one of patent validity: Can Hetero demonstrate by clear and convincing evidence that the asserted claims, particularly those directed to a specific polymorph, are invalid as obvious or anticipated in light of the state of the art of polymorph screening at the time of the invention?